4-aryl, 4-alkaryl-5-oxohexanoic acid



United States Patent 9 F in which R is an aryl radical, either unsubstituted or substituted, and R is an aralkyl radical, also either unsubstituted or substituted, particularly in the aryl moiety of the radical. Salts, esters, enol-lactones and amides of the above compounds are also contemplated within the scope of this invention as they are considered to be the equivalents of the acids because many of the derivatives exhibit the same therapeutic activity as the corresponding acid. It is hypothesized that the activity exhibited by the derivatives results from their conversion to the corresponding acid upon administration and that the free acid actually produces the therapeutic effect observed. As there is little difference therapeutically whether the acid, salt, ester, enol-lactone or amide is administered, all of these compounds are equivalent for the purpose of this invention. As the derivatives often have a different fate in the body as compared with the acid, it may be more advantageous to employ a salt, ester, enol-lactone or amide rather than the free acid because the derivative will often release the active form of the compound more slowly and certain of them will release the active form at a more advantageous site.

The ester, enol-lactone and amide derivatives will be described in more detail hereinafter. The only limitation to the type of salt is that it be non-toxic. Both Water soluble and Water insoluble salts are useful, depending upon the purpose for which salts of the compounds are to be employed. Insoluble salts are sometimes most useful when it is desired to take advantage of the repository efiects produced by compounds of this type, whereas soluble salts, especially water soluble salts, are usually better suited for use in oral preparations and other dosage forms designed for more rapid absorption into the blood stream.

It will be seen from the foregoing structural formula that all of the compounds of this invention contain an asymmetric carbon atoms, that is, the 4-position carbon atom to which the variable radicals R and R are attached. This is true not only of the hexanoic acids but also of the hexanenitrile intermediates and of each of the derivatives of the hexanoic acids hereinafter described. Because of the presence of this asymmetric carbon atom in the molecule, the racemic modification of the various products are obtained as the end products of the syntheses described. The optically active isomers can be separated by well known methods, if desired, and these individual antipodes can be employed to make subsequent derivatives having the same optical configuration if this is desired.

The compounds of this invention have utility as therapeutic agents, for example, as bactericidal, bacteriostatic, virucidal, and virustatic agents. Some of the novel compounds have shown marked activity as virustatic agents, particularly against organisms causing virus infections in the respiratory tract of man and animals.

Among the compounds having the general Formula l, those wherein R is a phenyl radical and R is a benzyl radical have been found generally to have better virustatic 3,MZ,714 Patented July 3, 1962 activity, and when R is the phenyl radical and R is a substituted benzyl radical, the virustatic activity appears to be enhanced markedly.

substituents suitable for attachment to the aryl portion of the phenyl and/ or the benzyl radical are halogens, e.g., chlorine, bromine, iodine or fluorine; lower alkyl, e.g., methyl, ethyl, propyl and the like; lower alkoxy, as methoxy, ethoxy, propoxy; nitro; carboxy; hydroxy; and hydroxy-alkyl groups. The phenyl and/ or the benzyl radicals can be substituted in the nuclear portion of either or both of them in ortho-, metaor para position, and monoor poly-substitution can be made in either or both of these radicals. When each of the aryl and aralkyl groups is monoor poly-substituted, or when either is poly-substituted, the substituents need not necessarily be the same. Any combination of substitution is suitable so long as it is chemically possible to introduce the selected radicals into the same nucleus. Ortho-substitution, particularly solely in the aryl portion of the benzyl radical, generally produces compounds having a high order of virustatic activity and, surprisingly, ortho-halogen substitution substantially increases the virustatic activity of these compounds. Especially marked virustatic activity is exhibited by the compound 4-(ortho-chlorobenzyl)-4-phenyl-5-oxohexanoic acid particularly against the PR8 strains of influenza. This compound, as well as others embraced by this invention, is also efiective against other strains of influenza virus as well as other viruses such as the infectious agent in mumps.

The compounds generally, and in particular 4-(orthochlorobenzyl)-4-phenyl-5-oxohexanoic acid, are effective upon oral administration. This is a distinct advantage especially in the treatment of virus infections of the upper respiratory tract. Administration is not restricted to the oral route, however, as the compounds can be administered parenterally if this is indicated.

The compounds of this invention are prepared by alkylation of phenylacetone or a nuclear-1y substituted derivative thereof to introduce the desired benzyl radical. Reaction readily occurs at the carbon atom which carries the phenyl radical. Cyanoethylation of the end product thus obtained produces the corresponding 4-phenyl-4-benzyl-5-oxohexanenitrile which, on hydrolysis, is converted to the desired 4-phenyl-4-benzyl-S-oxohexanoic acid. The individual reaction procedures are those conventionally employed to effect the same type of substitution in other compounds.

The salts and the ester, amide and enol-lactone derivatives are all prepared by known procedures.

In general, the salts are prepared by the action of an alkali metal hydroxide, an alkali'metal carbonate or bicarbonate, an amine or ammonia or the like on the 0x0- hexanoic acid.

The ester derivatives are readily prepared by allowing the selected 4-aryl-41ara1kyl-5-oxohexanoic acid toreact with the appropriate alcohol in the presence of esterificatie 131 catalysts, such as certain mineral acids, e.g., sulfuric acr The enol-lactone derivatives are prepared advantageously by interaction of the selected hexanoic acid with isopropenyl acetate.

Basic esters generally are prepared by reacting the enollactone with a (di-substituted-amino)-a1kanol.

And the amides advantageously are prepared by allowing the selected enol-lactone to react with the desired amine preferably with heating under reflux conditions.

The general method by which the compounds of this invention are prepared can be illustrated by the following reaction formulae:

The elements R and R in the above formulae have the meaning assigned to each of them above, R, R' and R-" respectively is an alkyl radical, advantageously a lower alkyl radical, and X is halogen or a similarly re active radical, e.g., a sulfonate ester radical and the like. Substantially all of the compounds illustrated by the structures identified by A to G'above are new compounds.

'Where'the starting muclearly substituted phenylacetone is unknown or not readily obtainable commercially, a suitable method for preparing it consists in condensing a benzaldehyde having the desired substituent on the phenyl nucleus with nitroethane, then reducing and simultaneou'sly hydrolyz'ing the resulting l-(substituted phenyD-2- nitropropene using iron and aqueous hydrochloric acid.

Another method which can be employed in preparing the nuclearly substituted phenylacetones consists in heating a phenylacetic acid having the desired substituent' or substituents attached to the phenyl nucleus with sodium: ace tate and acetic anhydride. O ther methodsimay be more suitable depending upon the .substituent or substituents one desires tohave attached to the phenyl nucleus. All

' of theseother methods are well known and would readily suggest themselves to a chemist desiring to prepare a particular nuclearly substituted phenyla cetone.

V The novel compounds of this invention are also useful as intermediates in preparing derivatives which have been found to have therapeutic activity. Derivatives ofpa'rticular interest in this respect are the heretofore unknown 4 aryl 4 aralkyl-1,3-cyclohexanediones. These compounds are often formed as by-productswhen the 4-ary1- 4-aralkyl-5-oxohexanenitriles are hydrolyzed to the corresponding acid. They can also be prepared from an derivatives are contained in the following examples, which are illustrative and in nowise limit the procedures by which they can be prepared to the'particular steps described. ,All physical constants are uncorrected values.

A. PREPARATION OF l-ARYL-l-ARALKYL-Z- PRQPANONES Example 1.] chloroben'zyl) 1-phenyl-2-pr0panone.-Flake sodiur n hydroxide of about 90% purity I H CHTC (F CHZ CH2TOOOH (C) (89 g., ca. 2 moles) was placed in a one-liter, four-necked, c R round-bottom flask equipped with'a mechanical stirrer, l5 dropping funnel, thermometer, and condenser protected H with a soda-lime drying tube. Phenylacet'o'ne (201.5 g., G.H3T.(D (|J ?HQ CH2 COQH+R OH 1.5 mole) and o-chlorobenz yl chloride (282 g., 1.75 mole) were thoroughly mixed and approximately 100' ml. of the H V mixture added to the reaction vessel with vigorous stirring. OHa-O(|3CH;OH2COOR The temperature rose to 5560 C. The reaction mixture was heatedon a steam bath to 70 C., and the ketone- V, 7 g o R CH2 V R o-o H l CHa-C(|3CHz.-CHa-COOH+ /COOCCH3 0 (i=0 (E) R CH3 7 V 1 R ens-#011,

r R\ 2CO\ R'\ j (I) V u/ o c 3=o+ N-Aik 1oH- orr3-o-( 3 orrronr-oo0A1k 1N (F RI 7 RI!!! 7 R! RI!!! 7 g 7 V s V Q 7 V ii i Rm o |3=o+ N'A1ky1NH CHz-C-(fi-CHz-GH OONH-Allryl-N (G) R uni-on, R 1 R a halide mixture added dropwise at a'rapid rate. The temperature rose to 90-95 C. and remained there about 15 minutes as addition was continued. The temperature then began to fall, even though addition was continued; therefore, the reaction vessel was heated on a steam bath in order to maintain a tempearture of90-100T C. Total addition time was minutes.

After addition was complete, the mixture was stirred and heated on a steam bath for 9' hours. The mixture then Was cooled and treated with water .(200 ml.) and benzene (1200 ml.). The mixture was stirred and acidified with concentrated hydrochloric acid. .The layers were separated and'the aqueous phase washed three times with 50' ml. portions of benzene and the aqueous phase discarded. The benzene extracts were combined with the original organic phase and dried over anhydrous sodium sulfate. After drying, the benzene was removed by reduced pressure distillation (water aspirator) and the resi- .ester of the 4-aryl-4-aralkyl-Swxohexanoic acid which is 1 readily converted to the 1,3.-cyclohexanedione derivative in the presence of a basic catalyst. .Another method has been discovered for the preparation' of these compounds in good yields. According to this method, the l-aryl-laralky1-2-propanones (compounds'A in the preceding reaction schemes) are allowed to react with beta-propiodue fractionated in vacuo. A total of 308 g. (79%) of l-(o-chlorobenzyl)-1-phenyl-2-propanone, boiling at 145-150 C. at. 1.5 mm. pressure, was collected (n =l.568l). Retractionation gave, a very good recovery of this product, B.P. 154-156. C. at 2.3 mm. pressure (n =1.5679). f

7 Example 2.] (0 biomobenzyl) -1-phenyl-2-propanone.--Potassium (3-1.6 g., 0.81 mole) wasadded to sodium-dried tertiary-butyl alcohol (700 ml.) in a twoliter, four-necked, round-bottom flask equipped with a mechanically driven Hirshberg stirrer, dropping funnel, thermometer, and reflux condenser. The potassium Was dissolved by warming andviolently agitating the mixture. The mixture was cooled and phenylacetone (108.8 g., 0.81 mole) was added in one portion. o-Bromobenzyl bromide (214.5 g., 0.86-mole) was dissolved in dry benzene ml.) and the mixture added dropwise over a period of 40 minutes, while thetemperature was main-+ .tained at 3540 C. The reaction mixture was stirred The solvent then was removed by distillation at reduced pressure and the residue treated with benzene (200 ml.) and water (200 ml.). The two layers were separated, and the aqueous layer was washed with benzene (50 ml.) The organic layers were combined and dried over sodium sulfate, and the solvent was removed by distillation. Fractional distillation of the residueat reduced pressure gave 205.3 g. (84%) of l-(o-bromobenzyl) -1-phenyl-2-propanone, B.P. 164-170 C. at 0.1 mm. pressure. Refractionation gave l-(o-bromobenzyl)-1-phenyl-2-propanone, Bl. 166-170 C. at 0.1 mm. pressure (n =l.5838).

Example 3. l-(o-chlorobenzyl) -1-(0-chlor0phenyl)- 2-propan0ne.-By replacing the phenylacetone and o-bromobenzyl bromide reactants employed in'Example 2 by o-chlorophenylacetone and o-chlorobenzyl chloride respectively, and following the same procedure described in Example 2, there was obtained a 78% yield of l-(ochlorobenzyl)-l-(o-chlorophenyl) -2-pr0panone, B.P. 1'61- 165 C. at 0.1 mm. pressure (n =1.5762).

Example 4. 1-(3,4-dichl0r0benzyl) -1-(4-chl0r0phen yl)-2-propanone.-By replacing the phenylacetone and the o-bromobenzyl bromide reactants employed in Example 2 by p-chlorophenylacetone and 3,4-dichlorobenzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained 1-( 3,4-dichlorobenzyl) l-(4-chlorophenyl) -2-prop anone.

Example 5. 1-benzyl-1-(3,4-dichl0rophenyl)-2-propanone.--By replacing the phenylacetone and the o-bromobenzyl bromide reactants in Example 2 by 3,4-dichlorophenylacetone and benzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained 1-benzyl-l-(3,4-dichlorophenyl) -2-prop anone.

Example 6.1-(2,4,6-trimethylbenzyl) -1-phenyl-2-propan0ne.-By replacing the o-bromobenzyl bromide reactant employed in Example 2 by 2,4,6-trimethylbenzyl chloride, and following substantially the same procedure described in Example 2, there was obtained an 81% yield of 1-(2,4,S-trimethylbenzyl)-1-phenyl-2-propanone, B.P. 160-165" C. at 0.3 mm. pressure, M. P. 5860 C.

Example 7.] 3,4,5 -trich lorobenzyl -phenyl-2 -pr0- pan0ne.By replacing the o-bromobenzyl bromide reactant employed in Example 2 by 3,4,5-trichlorobenzyl chloride (prepared by chlorination of the corresponding toluene), and following substantially the same procedure described in Example 2, there was obtained 1-(3,4,5-trichlorobenzyl)-l-phenyl-2-propanone.

Example 8. I-(p-propylbenzyl)-1-phenyl-2-pr0pan0ne.-By replacing the o-bromobenzyl bromide reactant employed in Example 2 by p-propylbenzyl cldoride (prepared by chloromethylation of propylbenzene), and following substantially the same procedure described in Example 2, there was obtained l-(p-propylbenzyl)-1-phenyl-2-propanone.

Example 9. J-(chlorobenzyl)-1-(p-ethylphenyl)-2- propanone-By replacing the phenylacetone and the o-bromobenzyl bromide reactants employed in Example 2 by p-ethylphenylacetone and p-chlorobenzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained l-(pchlorob enzyl) l- (p-ethyl) -2-prop anone.

Example 10. 1-(0-chl0robenzyl) -1-(p-methoxyphenyl)-2-propanone.-By replacing the phenylacetone and the o-bromobenzyl bromide employed in Example 2 by p-methoxyphenylacetone and o-chlorobenzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained 1-(0- chlorobenzyl) -1- (p-methoxyphenyl) -2-propanone.

Example 11.1-(p-eth0xybenzyl)-1(m-meihoxyphenyl)2pi0pan0ne.-By replacing the phenylacetone and the o-bromobenzyl bromide reactants employed in Example 2 by m-methoxyphenylacetone and p-ethoxybenzyl chloride (prepared by reducing p-ethoxybenzaldehyde to p-ethoxybenzyl alcohol followed by treatment with anhydrous hyd'rogen chloride to produce p-ethoxybenzyl chloride) respectively, and following substantially the same procedure described in Example 2, there was obtained 1 (p ethoxybenzyl) 1 (I11 methoxyphenyl)- 2-propanone.

Example 12.1-(m-methylbenzyl)-1-(0-methoxyphenyl)-2-propan0ne.-By replacing the phenylacetone and the o-b'romobenzyl bromide reactants employed in Example 2 by o-methoxyphenylacetone and m-methylbenzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained 1 (m methylbenzyl) 1 (o methoxyphenyl)- Z-propanone.

Example 13. I-benzyl-I-(o-chl0rophenyl)-2pr0pan0ne.By replacing the phenylacetone and the o-bromobenzyl bromide reactants employed in Example 2 by o-chlorophenylacetcne and benzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained a 933% yield of l-benzyll-(o-chlorophenyl)-2-propanone, Bl. -155 C. at 0.3 mm. pressure (n =l.5682).

Other l-aryl-l-aralkyl-Z-propanones, prepared by the process described in Examples 1 and 2, are identified in Table I. In each instance the alkylating agent, R'X, identified in the 3rd column of the table, was allowed to react with phenylacetone, thus forming a 1,1-disubstituted ketone having the structure Prepared by 13.1 0.] Ex.No. method of RX R M.P. 0. mm. Hg an Example No.

1 Eenzyl chloride benzyl 25.5-28.5 122-124/113 1 p-Chlorobenzyl chloride.-. p-ChlorobenzyL 79 -80 160-165/0. 2 1 3 tdmhlorobenzyl chloride 3,4-dichl0robcnzyl-.. 178-182/0 1 1. 5779 1 2 4 dichlorobenzyl chloride 2,4-dichlor0benzyl 69 70 -162/0 2 1 ethy1benzy1bromide m-Methylbenzyl 132-136/0 2 1.5555 1 o-Methylbenzyl bromide o-Methylbenzyl 142-146/0 15 2 o-Fluorobenzyl chloride o-Fluorobenzyl 28 28. 5 145-149/0. 25 1. 5455 2 2,6-dichlor0benzyl chl0ride- 2,6-t1ichl0robenzyl.-- 68 70 -165/0 1 2 o-Methoxybenzyl chloride.-- o-Methoxybenzyl 154-154/0 2 1. 5657 2 m-Cyanobenzyl bromide m-Cyanobenzyl- 67 69 -186/0. 2 2 m-Chlorobenzyl chloride m-Chlorobenzyl 157160/0.2 1, 5679 1 13.1. of crude material.

r v '7 V B. OF 4,4-DISIIBS'ITITUTED-5- OXOHEXANENTIRILES Example, 25. 4-(o chlorobenxyl)-4-phenyl- -oxohxanenitrile. l-(o chlorobenzyl) L 1 phenyl 2 pro- "panone (456 g., 1.76 mole),' prepared as described in Example 1, was dissolved in tertiary-butyl alcohol (1200 ml.) in a three-liter, three-necked, round-bottom flask fitted with a mechanical stirrer and dropping funnel. The catalyst, benzyltrimethylammoniumg hydroxide (2 fml. of 40% aqueous solution), was added. Acrylonitrile (112 g., 2.12 moles) then was added via a dropping funnel over a period of minutes while the solution was stirred and cooledso that the temperature remained below 30 C. Stirring was continued for 2 hours at room temperature and then lhourat 38-45 C. A periodic check on the pH of the reaction mixture was made to be sure that alkaline conditions were maintained. If the vsolution was not strongly alkaline throughout the reaction, more catalyst was added. The mixture was neutralized with sulfuric acid and the solid removed by filtration. 'It. is advisable to wash the product on the funnel with 'a small amount of cold isopropyl' alcohol. The 'yield of dry fl-(o-chlorobenzyl)-4-phenyl-5-oxohexane nitrile was 491 g. (90%), M.P. 103-106C. Recrystallization of the crude material fromisopropyl alcohol (ISOO- ml.) gave 457 gm. (85%) ofproduct, M.P. 104.5- 1 07, C. Further recrystallization gave material melting at 106-10 c.

The above procedure has been found to be most suitable for the preparation of the hexanenitrile compounds. Minor modifications have been made in order to provide the optimum reaction' conditions for cyanoethylation of any one particular ketone. For example, when more drastic reaction conditions are required to cyanoethylate a hindered ketone, the temperature is increased up to refluxing conditions, and the tertiary-butyl alcohol is replaced by acetronitrile or 1,.4-dioxane and the quaternary ammonium catalyst replaced by potassium hydroxide. The product may separate from the reaction mixture as a solid in good yields as described in Example 25 and it then is readily isolated and purified as indicated. In all other case the following modifications are made: When the reaction is complete, the catalyst is neutralized with acid, the solvent removed by distillation under reduced pressure, and the 4-aryl-4-aralkyl-5-oxohexanenitrile re covered by recrystallization when it is a solid or by distillation when it is a liquid. These modifications are well known to a chemist and are described here in order to minimize the amount of detailed description in the following examples. While each of the following examples describe the preparation of a panticular compound according to theprocessdescribed in Example 25, it is to be understood that the: above modifications were made when necessary.

. nitrile.

phenyl-Z-propanon'e employed in Example 25 by an equimolecular quantity of lbenzyl-l-(3,4-dichlorophenyl) -2- propanone, prepared as described in Exam'pIeQS, and tol- .-hexanenirrile.-'-By replacing the 1 (o chlorobenzyl) 1 oxohexanenitrile.-.By replacing the l-(o-chlorobenzyl) -1: phenyl-2propanone employed inExa'mple 25 by an'equimolecular quantity of1-(3,4,5-trichlorobenzyl)-l-phenyl- 2-propanone, prepared as described in-Example 7, and following substantially the same procedure described in Example 25, there was obtained 4-(3,4,5-t1richlorobenzyl)- 4-phenyl-5-oxohexanenitrile.

Example 29.-4(p-pr0pylbenzyl)4-phenyl-5-0x0hexanenitrile,-By replacing the l-(o-chlorobenzyD-l-phen: yl-2-propanone employed in Example .25 by an equimolecular quantity of l-(p-propylbenzyl)-l-phenyl-2-propanone, prepared as described in Example 8, and'following substantially the same procedure described in Example 25, there was obtained 4-(-p-propylbenzyl)-4-phenyl-5- oxohexanenitrile. 7

Example 30.-4 (p-chlorobenzyl) -4-'(p-ethylphenyl)- 5 -ox0hexanenit rile.By replacing the l-(o-chlorobenzyD- l-pheny-Lpropanone employed in Example 25 by an equimolecular quantity of l-(p-chlorobenzyl)el-(p-ethylphenyD-Z-propanone,prepared asp-described in Example 9, and following substantially the same procedure described in Example 25, there was obtained 4-(p-chlorobenzyl)- 4-(p-ethylphenyl)-5-oxohexanenitrile. a

' Example 31.--4-(0-chl0r0benzyl)-4(p meth0xyphen- 'yl)-5-oxohexanenitrile.--By replacing the l-(o-chlorobenzyl)-1-phenyl-2-propanone employed in Example 25 by an equimolecular quantity of 51-(p-ethoxybenzyl)-lmethoxyphenyl)-2-propanone, prepared as described in Example 10, and following substantially the same procedure described in Example 25, there was obtained 4-(0- chlorob enzyl) -4 (p-methoxyphenyl) -5-oxohexanenitrile.

Example 32.-4-(p-eth0xybenzyl)-4 (m-meth0xyphentvl)-5-0xohexanenit rile.---By replacing the vl-(o-chloro- .benzyl)-l-phenyl-2-propanone employed in Example 25 by an equimolecular quantity of l- (p-ethoxybenzyl)-l- (m-methoxyphenyl)-2-propanone, prepared as described in Example 11, and following substantially the same procedure described in Example 25, there was obtained 4-(pethoxybenzyl) -4 (m-methoxyphenyl) -5 -oxohexanenitrile.

Example 33.4-(m-methylbenzyl) -4-(o-m'ethoxyphenyl)-5 oxohexanenitrile.--By replacing the l-(o-chlorobenzyl)-l-phenyl-2-propanone employed in Example 25 by an equimolecular quantity'of 1-(m-methylbenzyl)-1- (o-methoxyphenyl) -2-propanone, prepared as described in Example .12, and following substantially the same procedure described in Example 25, there was obtained 4- (m methylbenzyl) 4 (o methoxyphenyl) -5 oxohexanenitrile. V I

Other 4-aryl-4-aralkyl-5-oxohexanenitriles, prepared by the process described in Example 25, are identified in Table II. Ineach instance the l-(o-chlorobenzyl)-l-phenyl-2-propanone employed in Example 25 was replaced by a ketone having the formula which was allowed to react with acrylonitrile by substantially' the'same procedure described in Example 25, thus yielding'a hexanenitrile having the formula The radicals R and R in the starting ketone in each case are retained in the hexanenitrile end product and are identified'in columns 2 and 3 of Table II.

Table II ll H I CHz-C-CH+CH:=CHCN CH3C*-COHECHr-CN it it Ex. Ketone of Bi. No. R R Example M.P. "C. C./nnn.

N0. Hg

Benzyl 14 127. -129 p-Chlorobenzyl 15 86 88 o-Fluorobenzyl 123. 5-125. 5 3, -dichlorobenzyl 16 105 107 2,4-dichlorobenzyl 17 88 91 2,6-diehlorobenzyh; 21 97. 5- 99. 5 m-Methylbenzyl 18 94. 5- 96 o-Methylbenzyl 19 88 90 2,4,6-trirnethylbenzyl 6 141 143 o-Methoxybenzyl 22 110 111 m-CyanobenzyL- 2 86 88 m-Chlorobenzyl 24 53. 5- 55.5

46- do o-Bromobenzyl 2 114 -115 47--- o-Ohlorophenyl.-- o-Ohlorobenzyl 3 48--- d n Benzy 13 124 l26 C. PREPARATION OF 4-ARYL-4-ARALKYL-5- OXOHEXANOIC ACIDS As indicated previously, the hexanenitriles of this invention contain an asymmetric carbon atom; therefore the racemic modification is produced in the synthesis. Hydrolysis of these hexanenitriles produces the corresponding racemic modification of the hexanoic acids. The following example describes a preferred method for hydrolyzing the hexanenitriles to the DL-hexanoic acids.

Example 49.4-(0-chl0r0benzyl)-4-phenyl-5 oxohexanoz'c acid.4 (o-chlorobenzyl)-4-phenyl-5-oxohexanenitrile (412.5 g., 1.32 mole), prepared as described in Ex ample 25, concentrated sulfuric acid (:0 1111.), glacial acetic acid (2 liters) and water (600 ml.) were placed in a five-liter, round-bottom flask and refluxed for l and hours. A sample of the reaction mixture was completely soluble in excess alkali. The mixture was poured with stirring into cold Water (8 liters). An oil separated which solidified upon stirring. The solid was filtered ofi, washed with water, dried, and pulverized; 415 g. (97%) of 4- (o-chlorobenzyl)-4-phenyl 5 oxohexanoie acid, MP. l06-125 C., was obtained. One recrystallization from acetonitrile (830 ml.) gave 354 gm. (81%), M.P. 124- '130" C. Further recrystallization gives material melting at 132-134" C.

Example 50.-4-(3,4-dichlorobenzyl)-4-(4-chl0rophenyl)-5-ox0hexan0z'c acid-By replacing the 4-(0-c'nlorobenzyl)-4-phenyl-5-oxohexanenitrile employed in Example 49 by an equimolecular quantity of 4-(3,4-dichlor0- benzyl)-4-(4-chlorophenyl)-5-oxohexanenitrile, prepared as described in Example 26, and following substantially the same procedure described in Example 49, there was obtained 4-(3,4-dichlorobenzy1) 4 (4 chlorophenyl)-5 oxohexanoic acid.

Example 51 .4 benzyl-4-(3,4-diclzlorophenyl) -5-oxohexanoic acid.By replacing the 4-(o-chlorobenzyl)-4- phenyl-S-oxohexaneuitrile employed in Example 49 by an equimolecular quantity of 4-benzyl-4-(3,4-dichlorophenyl) -5-oxohexanenitrile, prepared as described in Example 27, and following substantially the same procedure described in Example 49, there was obtained 4-benzyl-4- (3,4-dichlorophenyl) -5-oxohexanoic acid.

Example 52.4-(3,4,5-triclzl0r0benzyl)-4-phenyl-5-0xolzexanoz'c acid-By replacing the 4-(o-chlorobenZyl)-4- phenyLS-oxohexanenitrile employed in Example 49 by an equimolecular quantity of 4-(3,4,5-trichlorobenzyl)-4- phenyl-S-oxohexanenitrile, prepared as described in Example 28, and following substantially the same procedure described in Example 49, there was obtained 4-(3,4,5-trichlorobenzyl)-4-phenyl-5-oxohexanoic acid.

Example 53.4-(p-pr0pylbenzyl)-4-phenyl-5-0xohexanoic acid-By replacing the 4-(o-chlorobenzyl)-4-phenyl-S-oxohexanenitrile employed in Example 49 by an equimolecular quantity of 4-(p-propylbenzyl)-4-phenyl-5-oxohexanenitrile, prepared as described in Example 29, and following substantially the same procedure described in Example 49, there was obtained 4-(p-propylbenZyl)-4- phenyl-S-oxohexanoic acid.

Example 54.-4-(p-clzl0r0benzyl)-4-(p-ethylphenyl)-5- oxolzexanoz'c acid.-By replacing the 4-(o-chlorobenzyl)- 4-phenyl-5-oxohexanenitri1e employed in Example 49 by an equimolecular quantity of 4-(p-chlorobenzyl)-4-(pethylphenyl)-5-oxohexanenitrile, prepared as described in Example 30, and following substantially the same procedure described in Example 49, there was obtained 4-(pchlorobenzyl) -4- (p-ethylphenyl) -5-oxohexanoic acid.

Example 55 .-4-(0-chl0r0benzyl) -4-(p melhoxyphenyl)-5-0x0hexan0ic acid.-By replacing the 4-(o-chlorobenzyl)-4-phenyl-5-oxohexanenitrile employed in Example 49 by an equirnolecular quantity of 4-(o-chlorobenzyl)-4- (p-methoxyphenyl)-5-oxohexanenitrile, prepared as described in Example 31, and following substantially the same procedure described in Example 49, there was obtairied 4-(o-chlorobenzyl)-4-(p-methoxyphenyl) 5 0x0- hexanoic acid.

Example 56.4-(p-eth0xybenzyl)-4-(mmeth0xyphenyl)-S-oxohexanoic acid.By replacing the 4-(0-chlorobenzyl) -4-phenyl-5-oxohexanenitrile employed in Example 49 by an equimolecular quantity of 4-(p-ethoxybenzyl)- 4-(m-rnethoxyphenyl)-5-oxohexanenitrile, prepared as described in Example 32, and following substantially the same procedure described in Example 49, there was obtained 4-(p-ethoxybenzyl)-4-(m-methoxypheny1)-5 0x0- hexanoic acid.

Example 57.4-(m-methylbenzyl)-4-(0-meth0xyphenyl)-5-0xohexanoic acid.By replacing the 4-(0-chlorobenzyl) -4-phenyl-5-oxohexanenitrile employed in Example 49 by an equimolecular quantity of 4-(m-methylbenzyl)-4- (o-methoxyphenyl)-5-oxohexanenitrile, prepared as described in Example 33, and following substantially the same procedure described in Example 49, there was obtained 4-(n1-methylbenzyl)-4-(o-methoxyphenyl)-5 OX0- hexanoic acid.

Other hexanoic acids, prepared by hydrolyzing the hexanenitriles described in the preceding examples by the process described in Example 49, are identified in Table Ill. The radicals R and R in the starting hexanenitrile in most cases are retained in the corresponding hexanoic acid end product and are identified in columns 2'and 3 in Table III. An exception occurs when either or both of the radicals R and R contain a group, such as a cyano group, which is hydrolyzed under the conditions described in Example 49.

accent Table III it it OHS-C-C-CHz-CHrCN CH3--CCCHa-CHr-COOH Hexane- Reaction Ex. R R nitrile of time, Recrystallization solvent M.P. 0. N Example hours Benzyl 34 1 Isopropyl 'llinhnl I 143 144 5 o-wethoxy-benzyLnn 43 "2 Benzene-i-hexene,tolucne+hcptane,thcnaceticacid-l-HgO..- 110 113 o-Methyl-benzyl 41 1 Benzene-l-hexane,then'acetic acid+HzO 115 1l7 m-Methylbenzyl 40" 1% Cyclohexane, then ethyl acetate-kcyclohexana; 122. 5-124 p-ChlorobenzyL 35 2 Acetomtrile r 131 -132 5 3,4'dich1or0bcnzyL 37 1 Cyclohexanc, then carbon tetrachloride 117. 5-119 2,4-dieh1orobenzyl. 38 l Acetoru'tnle, then toluene 147 448. 5

2,6-dichlorobenzyL 39 l Toluene, then acetic acid; then ethyl acetate. 1645-166 m-Carboxybenzyl 1 44 2 Acetic acid, then n-butanol 239 -241 m-Chlorobenzyl- 45 "1 Acetomtrile I V 119 -121 do. o-Brornobenzyl i6 1 rln V r 122 123.5 70-. o-Ch1oropheny1 o-Chlor0benzyl; 47 1 179.5-18L5 71 do Benzyl 48 1 do 185 -187 1 R is m-cyanobenzyl in the hexancnitrile.

' The following examples are illustrative'of suitable meth- -ods for separating. the racemic modification torecover the le'vo-. and the dextro-forms of the hexanoic acids. As

. all of the racemic compounds described in Examples 49 through 71 can bejseparated' by the methods described below or by other well known methods, only a few repre- V sentative experiments are described" in detail.

Example 72 .-Levo-4-'(o-chloroljenzyl -4-phenyl-5 -0x0- hexanoic acid.Racemic-4-(o-chlorobenzyl)-4-phenyl-5- 'oxohexanoic acid (354.4 'g., 1.07 mole), prepared as de-' scribed in Example 49, and brucine alkaloid (422.6 g., 1.07 mole) were dissolved in warm methanol, seeded, and cooled for 24hours at room temperature andthen 24 hours at 5 C. The solid Was'filtered ofi'and'dried. (The *me thanolic mother liquor was set aside for recovery, by

the process described in Example '73, of the dextro-acid which remains in solution.) The yield was 351 g. of a solvate ofv the brucine salt of levo-4-(o-chlorobenzyl)-4- phenyLS-oxohexanoic acid, M.P. 97-101" C. One recrystallizationifrom methanol gave 300 g., M.P{100-102" C..

Two recrystallizations gave 289 'g., M.P. 100-102 C. Analysis indicates that this salt is solvated. Using calculations that adjust for the solvation, the specific rotation of pure brucine saltis about --87.9'for a 2% solution in 95% ethanol at C. The levo-acid brucine salt was dissolved in chloroform (liliter) and extracted with an excess of aqueous sodium hydroxide solution (1 liter containing 20g, 0.5 mole, of sodium hydroxide). Two more extractions of the chloroformphase with 100 ml.

portions of aqueous sodium hydroxide or the same '55 strength. were made. The combined aqueous extracts were treated with benzene (500 m1.) and'acidified with excess concentrated hydrochloric-acid. The mixture was acid. The mixture was shaken and theaqueous phase removedzand twice; extracted with 100 ml. portions of ben zene. I The combined benzene extracts were dried over anhydrous sodium sulfate and the solvent evaporated on a steam bath. The solid-was dried, yielding 120g. (70%) of levo-4-(o-chlorobenzyl)-4-phenyl 5-oxohexanoic acid, -M.P. l06109 C. Recrystallization from heptane gave 118.5 g.,M. P. '109-110.5C. A second recrystallization from heptane gave 116.5 g., M.P.l09-110.5 C. The

specific rotation of a 2% solution in 95% ethanol was 143.1 at 25 C. p

. Example 73. -Dextro'-4-(o-chlorobenzyl)-4-phenyl-5- oxohexzmoic acid-The methanolic mother liquor from which the brucine salt of the levo-acid separated (de scribed in Example 72) was evaporated to dryness at reduced pressure on a steam bath. The resulting oil was dissolved in chloroform (500 ml.) and extracted with an excess of aqueous sodium hydroxide solution ('1 liter containing 28 g., 0.7 mole, of sodium hydroxide). Two more extractions of the chloroformphase with 100 m1. portions of aqueous sodium hydroxide of the same strength were made. The combined aqueousextracts were acidified with excess concentrated hydrochloric acid and the mixture then extracted with benzene (500 mil). Two more extractions with benzene (100ml. portions) were made,

and then the combined benzene extracts were extracted with aqueous sodium hydroxide solution (1 liter containing 28 g., 0.7 mole, of sodium hydroxide). The aqueous layer was again acidified with excess concentrated hydrochloric acid and extracted with benzene (500 ml). The benzene solution was dried over sodium sulfate and then the benzene removed by evaporation. The resulting oil.

consisted of a mixture of thedextro-acid and the racemate. The oil was dissolved in acetonitrile (about 140 rnl.) and the solution cooled in the refrigerator overnight.

The solid that separated consists mainly of the racemic .modification. This material was removed by filtration,

and the filtrate was concentrated to dryness. The product solidified upon cooling. The .yield was 125 g., M.P. 97- 101 C. Recrystallization from heptane gave material 'm'elting at 100-103 C. The specific rotation of a 2% solution in ethanol was +l 27.5- at 25 0.; this "represents 'an optical purity of about 96%. Fractional scribed in Example '69, and preparing thebrucine salt of this latter product by substantially the same process described'in Example 72, there was obtained a 57% yield of' levo-4-(o-bromobenzyl) -4-phenyl-5-oxohexanoic acid which, after recrystallization from cyclohexane, melted at 85.5'87.5 C. The specific rotation of a 2% solution ofi'this product in 95% ethanol was 1 18;5 at 25 C.

13 The racemic modification of the other hexanoic acids described in Examples 49-71 can be separated by the process described in Example 72. Complete examples of the separation of each of them are not included because to do so would only lengthen the disclosure unduly without adding any material teaching to the art.

D. PREPARATION OF DERIVATIVES OF 4-ARYL-' 4-ARALKYL-5-OXOHEXANOIC ACIDS Most of the esters of the 4-aryl-4-aralkyl-5-oxohexanoic acids are advantageously prepared by dissolving the selected hexauoic acid in a mixture of absolute alcohol and concentrated sulfuric acid. An advantageous ratio is about 1 mole of the hexanoic acid, 2-2.5 liters of alcohol and 70-85 ml. of concentrated sulfuric acid. The mixture is then refluxed several hours, generally from 3 to 10 hours, under anhydrous conditions and the excess alcohol removed by distillation or evaporation. The residue, containing the crude ester, then is dissolved in about 200 ml. of benzene. The benzene solution is washed 2-5 times with 25 ml. portions of water and then 2-5 times with aqueous sodium bicarbonate. In some cases the ester may be isolated by pouring the reaction mixture into water and dissolving the material that sep-" arates in benzene. The benzene solution is dried advan-' tageously over sodium sulfate, and the solvent removed by distillation or evaporation.

The following example describes the above procedur for making esters of 4-aryl-4-aralkyl-5-hexanoic acid in more detail.

Example 75.-Methyl 4-benzyl-4-phenyl-5-oxohexan0- ate.4-benzyl-4-phenyl-5-oxohexanoic acid (50 g., 0.169 mole), prepared as described in Example 58, was dissolved in absolute methanol (200 ml.), and concentrated sulfuric acid (14 ml.) was added. The mixture was refluxed under anhydrous conditions for 7%. hours. The solution was cooled and poured into a liter of ice Water. An oil separated which soon solidified. The solid was filtered off, washed in water, and dissolved in benzene. The solution was washed with water, then with sodium bicarbonate solution, and again with Water. The benzene solution was dried over sodium sulfate and the benzene then removed by evaporation, yielding 52 g. (99%) of methyl 4-benzyl-4-phenyl-5-oxohexanoate, M.P. 89- 90 C. Further purification by distillation yielded a product having a boiling point of 15 8-1 60 C. at 0.5 mm. Upon recrystallization from hexane, the melting point remained essentially unchanged.

Example 76.Lev methyl 4 (o chlorobenzyl) 4- phenyl 0x0hexan0ate.Levo-4-(o-chlorobenzyl)-4- phenyl-S-oxohexanoic acid (100 g., 0.3 mole), obtained as described in Example 72, was dissolved in a solution of absolute methanol (400 ml.) and concentrated sulfuric acid (16 ml). The solution was refluxed under anhydrous conditions for seven hours. Most of the solvent was removed by reduced pressure distillation and the residue poured into water. The mixture was extracted three times with toluene (125 ml. portions) and the combined extracts were washed first with water, then saturated sodium bicarbonate solution and finally with water. After drying over anhydrous sodium sulfate, the solvent was removed by reduced pressure distillation. The residue was fractionally distilled at reduced pressure yield a total of 104 g. (87%) of material boiling at 187- 192 at 0.2 mm. pressure. Refractionation gave methyl 4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoate, boiling at 194-199 C. at 0.2 mm. pressure, n =l.562l.

Other esters of 4-aryl-4-aralkyl-S-oxohexanoic acid, identified in column C of Table IV, were prepared by allowing the hexanoic acid, identified in column A,- to react with the alcohol, identified in column 13, according to the procedure D1 and Example 75 above.

1 3- Table IV Reactants Hexanoic acid ester obtained 001. A 001. B 001. O

77- 4 (o chlorobenzyl) 4- Ethanol..- Ethyl 4- (o-chlorobenzyD- phenyl 5 oxohexanoic 4 phenyl 5 oxohexanoacid (Product of Ex. 49) e.

78-- 4-(o-bromobenzyD-4-phem Methanol- Methyl 4-(o-bromobenzyl) yl 5 oxohexanoic acid 4-phcnyl-5-oxohexanoate. (Product of Ex. 69)

79 4- (o methoxybenzyl) -4- do Methyl 4(o-mcthoxybenzphenyl 5 oxohexanoic yl) -4-phenyl-5-oxohexaacid (Product of Ex. 59) noate.

80 4 (o methylbenzyl) 4- l-propanoL 1 propyl 4 (o methylphenyl 5 oxohexanoic benzyl) 4 phenyl 5 acid (Product of Ex. oxohexanoate.

81-- 4 (o fluorobenzyl) 4 Methanol- Methyl 4 (o fluorobenzphenyl- 5 oxohexanoic yl) 4 phenyl 5 0x0- acid (Product of Ex. 63) hexanoate.

82-- 4 (2,4 dichlorobenzyl)- do Methyl 4 (2,4 dichloro- 4phenyl 5-oxohexanoic benzyl) 4 phenyl 5- acid (Product of Ex. oxohexanoate.

83- 4- (mcarboxybenzyl) 4- Ethanol. Ethyl 4-(m-carboethoxyphenyl 5 -oxohexanoic bcnzyl) 4 phenyl 5- acid (Product of Ex. 67) oxohexanoate.

84 4 (o chlorobenzyl) 4- MethanoL Methyl 4 (o chlorobenz- (o chlorophenyl) 5- yl)-4-(o-chlorophenyl)- oxohexanoic acid (Prodfi-oxohexanoate. uct of Ex.

85.- 4 benzyl 4 (3,4 dido- Methyl4benzyl-4- (3,4- chlorophenyl) 5 oxodichlorophenyl) 5 oxohexanoic acid (Product hcxanoate. of Ex. 51)

86-- 4-(3,4,5-triehlorobenzyl)- Ethanol..- Ethyl 4 (3,4,5 trichloro 4 phenyl 5 oxohexabenzyl) 4 phenyl 5- noic a)cid (Product of oxohexanoate.

87-- 4 (p propylbenzyl) 4- l-butanoL. 1-butyl4-(p-propylbenzyl) pheny1 5 oxohexanoic 4 phenyl 5 oxohexaacid (Product of Ex. 53) noate.

88 4 (p chlorobenzyl) 4- Ethanol... Ethyl 4-(p-chlorobenzyD- (p ethylphenyl) 5 4 (p ethylphenyl) -5- oxohexanoic acid (Prodoxohexanoate.

- not of Ex. 54)

89-- 4 (p ethoxybenzyl) 4- l-propanol. 1 propyl 4 (p ethoxy- (m methoxyphenyl) benzyl) -4- (m-methoxy- 6-oxohexanoic acid phenyl) 5 oxohexa- (Product of Ex. 56) noatc.

D2. 1,3-CYCLOHEXANEDIONE DERIVATIVES OF 4-ARYL- 4-ABALKYL-5-OXOHEXANOIC ACIDS The 1,3-cyclohexanedione derivatives of the 4-aryl-4- aralkyl-S-oxohexanoic acids can be prepared by various methods. The 1,3-cyclohexanedione derivative is often formed as a by-product when the 4-aryl-4-aralkyl-5-oxohexanenitriles are hydrolyzed to the corresponding acid. The 1,3-cyclohexanedione by-product may be formed regardless of whether the hydrolysis of the nitrile is conducted under acid or alkaline conditions. The cyclohexanedione product in general was separated from the hexanoic acid by making use of the difference in their solubility in organic solvents.

In addition, the 1,3-cyclohexanedione derivatives can be prepared from an ester of the 4-aryl-4-aralkyl-5-oxo- .hexanoic acid which is readily converted to the 1,3-cyclohexanedione in the presenceof sodium alkoxide or similar basic catalyst.

Another method by which the 1,3-cyclohexanediones can be prepared is by reaction of the l-aryl-l-aralkyl-Z- propanones with beta-propiolactone in the presence of certain condensing agents, such as potassium tertiarybutoxide. Optimum yields are obtained when an excess of beta-propiolactone and of the condensing agent are used. Very good yields have been obtained by employing 'a molar ratio of ketone to beta-propiolaotone to condensing agent of 1:25:25.

The following examples describe in more detail the above methods for making the 1,3-cyclohexanedione compounds.

Example 90.4 benzyl 4 phenyl 1,3-cycl0hexanedione.A one-liter, three-necked flask was fitted with a dropping funnel, mechanical stirrer, and reflux condenser capped with a drying tube. Absolute ethanol ml.)-

mljand benzene (250 ml.) with vigorousfstirring;

' l5 and sodium (6.0 g., 0.2 6 V H the flask. As soon as the sodium' had reacted, the excess alcohol was removed by distillation at reduced pressure.

while anhydrous conditions were maintained, then dry ether (100 ml.) was added. A solution of methyl 4- benzyl-4-phenyl-5-oxohexanoate (50.5 g., 0.163 mole),

prepared asidescribed inExample'75, dissolved in ether (4001111.) was added with stirring. A clear solution resill-ted, which soon began depositing a solid. After stirring for 18 hours at room temperature, the solution was refluxed for 4. hours.

mole) were introduced into.

Q from acetnitrile, the product melted at 158-1605" C.

The mixture was cooled and treated with water (300 ml.), which'dissolved the solid. 1 The ether layer was separated and extracted with sodium hydroxide (100 ml.).' The combined aqueous layers.

were acidified with excess concentrated hydrochloric acid.

The solid that separated was filtered off and washed with 1' water. The yield was 45 g. of 4-benzyl-4pl1enyl-1,3- cyclohexanedione, MP. 178-180" C. After recrystallization, firstfrom acetonitrile and then from ethyl acetate, the product melted at 181-1825, C. r

Example 91.4-(0-chl0robenzyl)4-(o-chlorophenyl) 4-phenyl-5-oxohexanoate employed in Example 90 by an equimolecular quantity of methyl 4-(o-chlorobenzyll-4- (o-chlorophenyl)-5-oxohexanoate, product of Example 84, therewas obtained 4-(o-chlo r'obenzyD-4-(o-chlorophenyl)-1,3-cyclohexanedione.

Example 92. 4 benzyl 4-(5 ,4-dichl 0r0phenyl)-1,3- byclohexanedione.-By replacing the methyl 4'-benzyl-4- phenyl-S-oxohexanoate employed in Example 90 by an equimolecular quantity of methyl 4-benzyl-4-(3,4-dichlorophenyl)-5-oxohexanoate, product of Example 85, there was obtained 4-benzyl-4-(3,4-dichlorophenyl)-1,3- cyclohexanedione. I f r Example 93.4-'(p-propylbenzyl) -4-phenyl-1,3-cyclohexan'edior'ze.By replacing the methyl 4-benzyl-4-phenyl- 5-oxohexanoate employed in Example 90 by an equimolecular quantity of l-butyl 4-(p-propylbenzyl)-4- phenyl-S-oxohexanoate, product of Example 87, there Was obtained 4 (p propylbenzyl) -4-phenyl-1,3-cyclohexanedione. Example 952-4:- (p-chlqrobenzyl)-4-(p-ethylphenyl)f 1,S-cyblohexanedi0ne.By replacing the methyl 4-benz yl- '4-phenyl-5-loxohexanoate employed in Example 90 by an equimolecular quantity of ethyl 4-(p chlorobenzyl)-4-(pethylphenyl)-5-oxohanoate, product of Example 88, there was obtained 4 (p-chlorobenzyl)-4-(p-ethylphenyl)- 'l,3 cyclohexanedione. j V I Example 95 .-4- (p-ethoxybenz'yl) -4- (m-methoxyphem yl) -1,3-cycl 0hexandi0'ne.-By replacing the methyl 4- 'benzyl-4-pl1enyl-S-oxohexanoate employed in Example 90 by an equimolecular quantity of -1-propyl 4-(p-ethoxybenzyl)-4-(m-methoxyphenyl) 5-oxohexanoate, product of Example 89, there was obtained 4- (p-eth0xybenzyl) 4- Example 97 4-(o-me thylben'zyl) -4-ph'enyl-1,3-cycl0- hexanedi0ne.-A solution of potassium tertiary-butoxide was prepared by allowing potassium (6.6 g., 0.169 mole) to'reactwith dry tertiary-butyl alcohol (175 ml.) under anhydrous conditions. While stirring, the solution was treated with 1-(o-methylbenzyl)-l:phenyl-2-propanone (16.1 'g.,*0.0677 mole); obtained. as 'de'scribed'in Example 19,-'in"tcrtiary-butyl alcohol 1111.). A solution'of beta-propiolactorie (12.2 g., 0.169 mole) in tertiaryrbutyl alcohol (50 ml.) w s added, drQPWise with stirring, over 15 minutes. The temperature Wasi'kept at 38-42" C. during the addition by cooling when necessary.

" After the addition was complete, the mixture was refiuxed for -2 hours" and the solvent then was removed by distillationjat, reduced pressure. 'The residuewas treated with water (150 m1.) and benzene (75 1111.)? After shak ing,'jthe layers were separated. The benzene layer was extracted with 5% potassium hydroxide. (100 ml.) The combined aqueous extracts were treated with decolorizing charcoal, filteredand' acidified with concentrated hydrochloric acid; The oil that separated soon solidified. The solid was removed by filtration and washed with a small amount of hexanej The yield offcrude product was 14.9 g. (75%). Two recrystallizations from a small volume of acetonitrile gave 4-(o-methylbenzyl)-4phenyl-1,3 cyclohexanedione melting at 177-179" C. r

Other 1,3-cyc'lohexa'nedione derivatives, which were I ob ained either as byproducts during the hydrolysis of the hexanediona.-In a two-liter, four-necked, round-bottom was added dropwise over 1 hour at 25-289 C. The mixture was refiuxedon a steam bath for 1 /2 hours; then -the solvent was removed by distillation "at reducedpressure. The viscous residue was treated with water (500 The layers were separated and the aqueous layer extracted withbenzene (100 ml.). The combined organic layers fia sk fitted with a reflux condenser (protected withadry- 4-1aryl-4 aralkyl-5-oxohexanenitriles to the corresponding carboxylic acids why the reaction of a l-aryl-l-aralkyl Z-propanone with beta-propiolactone, are identified in the following Table V. V V

' V T able V I! /C'-CH2 V '70:0 R" our-om 7 Ex. R 5' Re'adnba'mimd M.P.O.

'98.; Thenyl m-Methylbcnzyh- Preparedbythepro- 168 1695 cess described in I Example 97. 99; clo p-Ohl0robenzyl By-product'of acid 220 221.5 r 1 I hydrolysis dep scribedin Example 62. 100 d0 3, l-dichlorobenzyl By-product of ac d 2 173 7 hydrolysis described in Ex-' I ample 64. V 101 "do---" o-Bromobeuzyl By productof acid 154.5 156 hydrolysis described in Example 69.

' D3. ENOL-LACTONES OF 4-ARYL-4-ARALKYL-5- OXOHEXANOIC ACIDS The enol-lactone derivatives are made as follows: A

; continuedfor 2-3 hours, and the residue. then'is' transferred to aflash suitably equipped for distillation at'reduced pressure. After distillation of the by-p'roducts and .unreacted isopropenyl acetate,.the enol-lactone can be iso- 17 lated from the undistilled residue or it can be purified by distillation.

The following example is a detailed procedure for making the enol-lactone derivatives by the above method.

Example 102.4(0-chlor0benzyl) 4 phenyl 5 hydroxy 5 hexenoic acid lactone.4-(o-ch1orobenzyl)-4- phenyl-S-oxohexanoic acid (82.7 g., 0.25 mole), product of Example 49, isopropenyl acetate (75.1 g., 0.75 mole), and concentrated sulfuric acid (3 drops) were placed in a flask with a long fractionating column connected to a downwardly directed condenser. The mixture was heated by means of a mantle over a period of 2 hours so that a slow distillation occurred. A total of 33.5 ml. of distillate boiling at 55-59 C. was collected. This material was discarded and the residue distilled at reduced pressure. A yield of 66 g. (78%) of 4(o-chlorobenzyl-4-phenyl-5- hydroxy-S-hexenoic acid lactone, B.P. 196-204 C. at 0.1 mm. pressure, M.P. 126-l32 C. was obtained. Upon recrystallization from toluene and then hexane, the prod uct melted at 134.5-136" C.

Example 103. Levo-4-(o-chlorobenzyl) -4-phenyl-5- hydroxy-S-hexenoic acid laclne.-lsopropenyl acetate (100 g., 1 mole) and levo-4-(o-chlorobenzyl)-4-phenyl- 5-oxohexanoic acid (80 g., 0.24 mole), obtained as described in Example 72, were placed in a flask equipped with a long fractionating column and concentrated sulfuric acid (3 drops) was added. A downwardly directed condenser was attached to the side arm and the mixture was gently heated so that a slow distillation occurred. A total of 30 ml. of'material, boiling at 56-59 C., was collected during two hours. Another drop of concentrated sulfuric acid was added to the reaction mixture and heating was continued for another 30 minutes; however, only a very little more distillate was collected.

Volatile materials were removed by distilling the residue on a steam bath at reduced pressure. The residue then was fractionated in an ordinary Claisen flask. A total of 63 g. (84%) of material, boiling at 205-2l2 C. at 0.2 mm., was collected. Theproduct was fractionated a second time and the solid which formed on standing was recrystallized first from cyclohexane then twice from heptane. Levo-4-(o-chlorobenzyl)-4-phenyl-5-hydroxy-5-hexenoic acid lactone was obtained as a crystalline product melting at 113-1135 C. (uncona), the specific rotation of a 3% solution in toluene at 25 C. was 382.2.

Other compounds, identified in Table VI below, were prepared by the above described method. The starting 7 materials are identified in column 2, and the enol-lactone produced is identified in column 3.

Table VI Starting material Enol-lactone 4- (o-bromobenzyl) -4-phenyl-5- 'oxonexanolc acid (Product of 4- (m-methylbenzyl) -4-phenyl- 5-oxohexanoic acid (Product of Ex. 61).

4- (o-fiuorobenzyl) -4-phenyl-5- oxohexanoic acid (Product of 4(2,6-dichlorobenzyl)-4-pheny1- 5-oxohexanoic acid (Product of Ex. 66).

4-(111- chlorobenzyl) -4-phenylfi-oxohexanoic acid (Product of Ex. 68).

4-benzyl-4-(o-chlorophenyl)-5- oxohelxanoic acid' (Product of 4 (3,4 dichlorobenzyl) 4 (4 chlorophenyl)-5-oxohexanoic acid (Product of Ex. 50).

4-(p propylbenzyl)-4-phenyl-5- oxohexanoie acid (Product of Ex. 53).

104- 4- (o-bromobenzyl) -4-phenyl-.5-

tone.

4- (m-methylbenzyl) -4- phenyl- 5-hydroxy-5-hexenoic acid lactone.

no. 4(2 6-dichlorobenzyD-4-phenyl- 'dhydroxy-S-hexenoic acid lactone. 4- (m chlorobenzyl) 4 phenyl 5-hydroxy-5-hexenoic acid lactone.

4-benzy1-4- (o-chlorophenyl) -5- lgydroxy-fi-hexenoic acid lacno. 4 (3,4 dichlorobenzyl) 4 (4 chloro-phenyl) 5-hydroxy-5- hexenoic acid lactone. 1l1..

hydroxy-B-hexenoic acid lactone.

Table VI-Continued Starting material Enol-lactone 4- (o-chlorobenzyl) -4- (p-methoxyphenyl)-5-hydroxy-5-hexenoic acid lactone.

4- (m-methylbenzyl) -4- (o-methoxyphenyl)-5-hydroxy-5-hexenoic acid lactone.

4- (0- chlorobenzyl) -4- (0- chlorophenyl)-5-hydroxy5-hexenoic acid lactone.

4-benzy1-4- (3,4-diohlorophenyh- 5-hydroxy-5-hexenoic acid lactone.

4 (3,4,5 trichlorobenzyl) 4 phenyl- 5-hydroxy-5-hexenoic acid lactone.

4- (pchlorobenzyl) -4- (p-ethylphenyl)-5-hydroxy-5-hexeno1c acid lactone.

4-benzyl 4- phenyl- 5- hydroxy- S-hexenoic acid lactone.

hydroxy-5-hexenoie acid 130- hydroxy-5-hexenoic acid lacsolution of 10% benzene in cyclohexane.

4- (3 4-dichlorobenzyl)-4 phenyl- 5- ydroxy-fi-hexenoic acid lactone.

119 4-(3,4-dichlorobenzyl)-4-phenyl- 5-oxohexanoic acid (Product of EX. 64).

D4. BASIC ESTERS OF '4-ARYL-4-ARALKYL-5- OXOHEXANOIC' ACIDS The basic esters of the hexanoic acids of this invention are readily prepared by first converting the desired 4-aryl- 4-aralkyl-5-oxohexanoic acid to the corresponding enollactone by the procedure described in D3 above and then heating the enol-lactone with the desired (di-substituted 'amino)-alkanol, which is generally used in excess. The enol-lactone can be dissolved in the selected (di-substituted-amino)-alkanol when the alkanol is a liquid, and in the event the alkanol is a solid, then the alkanol can be melted and the enol-lactone dissolved therein or the enollactone and the (di-substituted-amino)-alkanol can be dissolved in a common inert solvent. The solution, however made, is then heated preferably under anhydrous conditions and often conveniently refluxed for several hours. The excess (di-substituted-amino) -alkanol then is distilled oil and the residue, the basic ester, purified according to conventional methods.

The following example describes the process for making the basic esters of the hexanoic acids of this invention in more detail.

Example 120.2-dimethylaminoethyl 4-(0-chl0robenzyl)-4-phenyl- -ox0hexanoate hydr0br0mide.4-(ochlorobenzyl)-4-phenyl-S-hydroxy-S-hexenoic acid lactone (36.1 g., 0.115 mole), product of :Example 102, was dissolved in dry Z-dimethylaminoethanol (89 g., 1.0 mole) and the mixture heated under anhydrous conditions for 30 minutes at 95 C. and then refluxed for 2 hours. The excess amine was removed by distillation at reduced pressure and the residue dissolved in benzene (250 1111.). The solution was washed twice with water and then dried over sodium sulfate. The solvent was removed by distillation at reduced pressure and the residue dissolved in cyclohexane (150 ml.)

Dry hydrogen bromide was passed through the solution until precipitation no longer occurred. The precipitated product was a sticky, semi-solid material. Addition of benzene (50 ml.) and kneading the mixture produced a white solid. The solid was filtered ofi and washed with a The product was dried in a vacuum desiccator over phosphorus pentoxide (P 0 The yield of dry Z-dimethylaminoethyl 4- (o-chlorobenzyl)-4-phenyl-5-oxohexanoate hydrobromide was 48.2 g. (87%), M.P. 144l48 C. Recrystallization from isopropyl alcohol (150 ml.) gave 43.6 g., M.P. 149-15l C. A second recrystallization gave 41.7 g.,

- M.P. 149-151" C.

Other basic esters, identified in column 5 of Table VII,

4- (p-propylbenzyl) -4-phenyl-5- amino)-alkanol identified in column 4 with or without an inert solvent and heating the mixture, thus producing the basic ester identified in column 5.

general formula and alkali metal salts thereof wherein Y is selected from o the group consisting of hydrogen, halogen, lower alkyl,

g l lower alkoxy and carboxy groups. 4. A 4,4-disubstituted-5-oxohexanoic acid having the 5 general formula and alkali metal salts thereof wherein R is a mononuclear aryl radical and R is a mononuclear arylmethyl radical;

2. A 4,4-disubstituted-5-0xohexanoic acid having the general formula v 0 q em-ii-aL-om-om-c 0 OH CH 0 z- -CCH:OHQC 0 OH halogen and alkali metal salts thereof. CH 5. 4-(o-ehlorobenzyl)-4-phenyl-5-oxohexanoic acid.

6. Levo 4 (o-chlorobenzyl)-4-phenyl-5-oxohexanoic Yn acid. and alkali metal salts thereof wherein Y is selected from the group consisting of hydrogen halogen, lower alkyl References Cited 1n the file of thrs patent lower alkoxy and carboxy groups; and n is a whole num- UNITED STATES PATENTS ber selected from 1 t0 3. 17 B 9 3. A 4,4-disubstituted-5-oxohexanoic acid having the 25 2 32;? gg gg 'g 'gi:Iiltj; 32?; i general fmmfla 2,563,820 Darragh et a1. Aug. 14, 1951 2,586,486 Schwartzman Feb. 19, 1952 GHQ 

1. A 4,4-DISBUSTITUTED-5-OXOHEXANIOIC ACID HAVING THE GENERAL FORMULA 